'Resonance' may explain virologic failure in STI drug therapy

Researchers have been puzzled over why HIV-positive patients who have periodic, built in interruptions in their drug therapy reach a point where the therapy no longer reduces their viral loads, even in the absence of any evidence of acquired drug resistance.

Now two UCLA AIDS Institute researchers have devised a novel hypothesis based upon mathematical modeling to be published in the April 15 issue of the medical journal The Lancet - one linked to the physical phenomenon known as "resonance." Based on the assumption that viral dynamics have an intrinsic periodicity, or cycle, that varies from patient to patient, the researchers suggest that these forces interact with therapeutically prescribed, structured treatment interruptions (STI) in a way that causes high fluctuations in the patient's viral load and, ultimately, virologic failure. At that point, the drugs can no longer reduce the levels of virus in the patient's blood.

Thus, UCLA researchers feel there may not be a single, structured treatment interruption therapy that will be effective for all HIV patients.

"This is important to keep in mind when developing therapies for HIV-patients," said Dr. Sally Blower, professor of biomathematics and co-author of the study with Romulus Breban, postdoctoral researcher.

"Our research shows that mathematical models can be extremely useful as tools for generating hypotheses," Blower said.

Resonance is the oscillation that results when a system with natural periodicity is affected by an external force that is itself moving at an appropriate frequency, resulting in a strong fluctuation. A swing pushed in the same direction in which it is already moving, for instance, will swing higher as a result of that force placed upon it at a frequency that corresponds to the natural periodicity of the swing.

In the same way, the periodic interruptions in HIV anti-retroviral therapy might contribute toward pushing the viral load higher when those interruptions occur at a specific time during the viral load's cycle, the researchers suggest. Resonance is observed when the anti retroviral drugs cannot reduce the viral load.

"Resonance is a very general phenomenon that has been long known in physics and engineering," Breban said. "We are the first to apply it to virology."

"At the beginning of treatment, the patient's viral load is quickly suppressed," Breban said. "But the therapy interruptions combined with the viral dynamics, which can vary widely from person to person, can lead to treatment failure."

Structured therapy interruptions have up to now been used only in clinical trials, not in clinical practice. STI programs have been designed on a variety of schedules. Advantages to these approaches, if they worked, would be that they would demonstrably keep viral loads low while also reducing toxicity and costs. The latter would be particularly beneficial in developing countries with high rates of HIV infection, where both money and drugs are in short supply.

While initial pilot studies into STI regimens showed no virologic failure in the test subjects, a large-scale clinical trial in 2003 was prematurely terminated due to a 53 percent virologic failure rate. And these disappointing findings have continued into the present year, prompting authorities to cancel another test of STI. On Jan. 18, the National Institute of Allergy and Infectious Diseases halted enrollment into an international HIV/AIDS trial known as Strategies for Management of Anti-Retroviral Therapy, which compared continuous antiretroviral therapy with episodic drug treatments, after researchers determined that patients on episodic treatment faced more than double the risk of disease progression than the other patients.

If the resonance hypothesis to STI is correct, then the results of the Blower/Breban study have important implications for the treatment of patients, clinical trial design and public health.